This invention relates to the novel use of imidazole compounds in the treatment of stroke and stroke management.
Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock, syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter""s syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic xcex2 cells.
Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews the biological activities which have been attributed to IL-1. It should be noted that some of these effects have been described by others as indirect effects of IL-1.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyresis.
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have been applied to IL-8, such as neutrophil attractant/activation protein-1(NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration.
IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
There remains a need for the treatment, and for the prevention of CNS injuries which are related to the ability of compounds which are cytokine suppressive, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.
This invention relates to the use of substituted imidazole compounds, or pharmaceutical compositions thereof in the treatment of stroke, and stroke management.
The compounds for use herein are described in PCT[US97/09888 filed Jun. 6, 1997, and published Dec. 18, 1997 as WO 97/47618, Liverton et al., now U.S. Pat. No. 5,859,041 granted Jan. 12, 1999, whose disclosures are incorporated herein by reference in their entirety.
The present invention is to the novel use of the compounds described in WO 97/47618 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries.
Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/47899 (PCT/US98/07831), Dodd et al., for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/52937 (PCT/US98/10807), Anantanarayan et al., now U.S. Pat. No. 5,932,576, granted Aug. 3, 1999; U.S. Pat. No. 6,0874,96, and U.S. Pat. No. 6,335,336 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent and patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 99/03837 (PCT/US98/13419), Wachter et al., now U.S. Pat. No. 6,040,320 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/47892 (PCT/US98/07910), Beers et al., now U.S. Pat. No. 5,965,583 and U.S. Pat. No. 6,214,830 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 99/01449 (PCT/EP98/03930), Revesz et al., now U.S. Pat. No. 6,300,347 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/52941 (PCT/US98/11684), Hanson et al., now U.S. Pat. No. 6,087,381 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/52941 (PCT/US98/11684), Hanson.et al., for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 97/05878 (PCT/US96/12922), De Laszlo et al;, now U.S. Pat. No. 5,837,719, granted Nov. 17, 1998, for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent and patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 97/16441 (PCT/US96/17324), De Laszlo et al., for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/21957 (PCT/US97/21019), Chang et al., now U.S. Pat. No. 5,955,480 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 97/12876 (PCT/US96/15880), now U.S. Pat. No. 5,717,100, granted Feb. 10, 1998, Selnick et al., and U.S. Pat. No. 6,083,949 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 97/16426 (PCT/US96/17477), De Laszlo et al., for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 97/05877 (PCT/US96/12917), De Laszlo et al., now U.S. Pat. No. 5,782,778, granted Aug. 11, 1998, for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 97/16442 (PCT/US96/18539), De Laszlo et al., for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 98/52940 (PCT/US98/10436), Anantanarayan et al., now U.S. Pat. No. 6,423,713 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
Another aspect of the present invention relates to the novel use of compounds described in WO 99/20624 (PCT/EP98/06472) Cheng et al., now U.S. Pat. No. 6,316,464, U.S. Pat. No. 6,479,507 for the treatment, an acute setting, as well as including prophylactic use, in preventing in those individuals deemed susceptible to, various CNS injuries. Synthetic chemistry, dosages, and methods of making pharmaceutical formulations thereof are also contained within the noted patent application.
CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel. The role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
In addition to the advantage of using a compound which is an inhibitor of cytokine suppressive binding protein activity (CSBP) for the inhibition of IL-1 or TNF alone which is neuroprotective, inhibition of both cytokines provides for increased efficacy. These compounds may also be useful for all types of strokes, regardless of the thrombotic/hemorrhagic variants. This would allow for early intervention, possible without use of CAT scans, and potential use in conjugation with tPA, or streptokinase, for instance.
TNF-xcex1 is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression. Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25.; No. 7, pp. 1481-88 (1994) whose disclosure is incorporated herein by reference.
Models of closed head injuries and treatment with mixed 5-LO/CO agents is discussed in Shohami et al., J. of Vaisc and Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure is incorporated herein by reference. Treatment which reduced edema formation was found to improve functional outcome in those animals treated.
As noted, these compounds are useful as cytokine inhibitors, and in particular the preferred method of inhibition is the inhibition of the CSBP/p38/RK kinase pathway. A description of the assay for inhibition of the cytokine specific binding protein (CSBP) is also found in WO 95/07922, whose disclosure is incorporated by reference in its entirety, as well as in U.S. Pat. No. 5,777,097. A kinase binding assay is also described herein. Updated versions of a CSBP kinase assay may be found in later filed SB patent applications including WO 98/57966 for instance.
The compounds of WO 97/47618 can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by a neurotraumatic event, such as closed head injuries.
In addition, the compounds of WO 99/20624, WO 98/52940, WO 97/16442, WO 97/05877, WO 97/16426, WO 97/12876, WO 98/21957, WO 97/16441, WO 97/05878, WO 98/52941, WO 99/01449, WO 98/47892, WO 99/03837, WO 98/52937, and WO 98/47899, can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by a neurotraumatic event, such as closed head injuries.
The compounds of these patent applications are capable of inhibiting proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use in therapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these pro-inflammatory cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
Accordingly, the present invention provides for a method of treating a neurotraumatic disease, in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a CSAID(trademark), cytokine suppressive inhibitory compound, wherein the compound is an inhibitor of the CSBP/p38/RK kinase.
As used herein, the term xe2x80x9cinhibiting the production of IL-1 (IL-6, IL-8 or TNF)xe2x80x9d refers to:
a) a decrease of excessive in 3in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by all cells, including but not limited to monocytes or macrophages;
b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels;
c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or
d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels.
As used herein, the term xe2x80x9ccytokine interferingxe2x80x9d or xe2x80x9ccytokine suppressive amountxe2x80x9d refers to an effective amount of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
A new member of the MAP kinase family, alternatively termed CSBP, p38, or RK, has been identified, See Lee et al., Nature, Vol. 300 n(72), 739-746 (1994). Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin-1 and tumor necrosis factor. The cytokine biosynthesis inhibitors, of the present invention, compounds of Formula (I), have been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors are of aid in determining the signaling pathways involvement in inflammatory responses.